Activated hepatic stellate cells promote liver cancer by induction of myeloid-derived suppressor cells through cyclooxygenase-2
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Yaping Xu1,2,*, Wenxiu Zhao1,*, Jianfeng Xu1, Jie Li1, Zaifa Hong1, Zhenyu Yin1 and Xiaomin Wang1
1 Department of Hepatobiliary Surgery, Zhongshan Hospital, Xiamen University, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma (Xiamen University Affiliated Zhongshan Hospital), Xiamen, Fujian, China
2 Department of Basic Medicine, Xiamen Medicine College, Fujian, China
* These authors have contributed equally to this work
Xiaomin Wang, email:
Zhenyu Yin, email:
Keywords: myeloid-derived suppressor cells, hepatic stellate cell, cyclooxygenase 2, hepatocellular carcinoma, prostaglandin 2
Received: March 04, 2015 Accepted: December 12, 2015 Published: January 07, 2016
Hepatic stellate cells (HSCs) are critical mediators of immunosuppression and the pathogenesis of hepatocellular carcinoma (HCC). Our previous work indicates that HSCs promote HCC progression by enhancing immunosuppressive cell populations including myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). MDSCs are induced by inflammatory cytokines (e.g., prostaglandins) and are important in immune suppression. However, how HSCs mediate expansion of MDSCs is uncertain. Thus, we studied activated HSCs that could induce MDSCs from bone marrow cells and noted that HSC-induced MDSCs up-regulated immunosuppressive activity via iNOS, Arg-1, and IL-4Rα. After treating cells with a COX-2 inhibitor or an EP4 antagonist, we established that HSC-induced MDSC accumulation was mediated by the COX2-PGE2-EP4 signaling. Furthermore, in vivo animal studies confirmed that inhibition of HSC-derived PGE2 could inhibit HSC-induced MDSC accumulation and HCC growth. Thus, our data show that HSCs are required for MDSC accumulation mediated by the COX2-PGE2-EP4 pathway, and these data are the first to link HSC and MDSC subsets in HCC immune microenvironment and provide a rationale for targeting PGE2 signaling for HCC therapy.
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